Four new Y-type actinomycin analogues named Y6-Y9 (1-4) were isolated and characterized from the scale-up fermentation of the Streptomyces sp. strain Gö-GS12, as well as actinomycin Zp (5), which was, for the first time, isolated as a natural product. Structures of the new compounds were elucidated by the cumulative analyses of NMR spectroscopy and HRMS. The 4-hydroxythreonine on the β-ring of 1 uniquely undergoes both a rearrangement by a 2-fold acyl shift and an additional ring closure with the amino group of the phenoxazinone chromophore, and the α-rings of 4 and 5 contain a rare 5-methyl proline. Compounds 2-5 showed potent antibacterial activities against Gram-positive bacteria that correlated with cytotoxicity against representative human cell lines. The combination of a β-ring rearrangement and additional ring closure in 1 rendered this actinomycin significantly less potent relative to the nonrearranged comparator actinomycin Y5 and other actinomycins.
|Number of pages||9|
|Journal||Journal of Natural Products|
|State||Published - Oct 28 2016|
Bibliographical noteFunding Information:
This work was supported in part by the National Institutes of Health Grants AI087849 (S.V.L.), AI52188 (J.S.T.), and OD21479 (J.S.T.); the National Center for Advancing Translational Sciences Grant UL1TR000117 (S.V.L. and J.S.T.); the University of Kentucky College of Pharmacy (S.V.L. and J.S.T.); and the University of Kentucky Markey Cancer Center (J.S.T.)
© 2016 The American Chemical Society and American Society of Pharmacognosy.
ASJC Scopus subject areas
- Analytical Chemistry
- Molecular Medicine
- Pharmaceutical Science
- Drug Discovery
- Complementary and alternative medicine
- Organic Chemistry